Pain is the most frequently reported symptom and is a common clinical problem which confronts the clinician. Millions of people in the United States suffer from severe pain that, according to numerous recent reports, is chronically under-treated or inappropriately managed.
Opioids have long been recognized as one of the most effective treatments of pain. However, they also have a high potential of abuse. In fact, opioid and narcotic abuse are major worldwide problems connected with tremendous social and personal strife. As of 1992, the estimated United States economic cost of drug and alcohol abuse was $246 billion. The latest National Household Survey on Drug Abuse survey conducted by the Substance Abuse and Mental Health Services Administration reported in July 2007 that nearly one in twelve full-time workers in the United States have serious enough drug/alcohol problems to require medical treatment. Providing recovery assistance for drug addicts and alcoholics with pharmacological interventions has proven helpful.
Certain opioids, such as buprenorphine, butorphanol, dezocine, meptazinol, nalbuphine, and pentazocine, have both agonist and antagonist qualities. For example, the main agonist/antagonist effect of buprenorphine is through its binding to μ-opioid and κ-opioid receptors, acting clinically as an agonist at lower doses and as an antagonist at higher doses. The dual agonist-antagonist activity of these opioids make them effective at not only treating pain, but also at reducing the severity of the withdrawal symptoms experienced when a former abuser begins to eliminate opioid and/or alcohol. Buprenorphine is currently available as a sublingual dosage form, both alone (Subutex®) and in combination with naloxone (Suboxone®) for the treatment of pain and opioid dependence. Because they are administered sublingually, both have clinically relevant drawbacks. For example, the necessity of taking multiple daily doses, or even once-daily dosing, decreases patient compliance. In addition, the daily and multiple daily dosing necessary with sublingual dosage forms may cause more frequent and more extreme peaks and troughs in the blood-plasma concentration of the active medications, thereby, increasing the potential for a patient to experience both the adverse effects associated with supra-therapeutic concentrations and ineffective relief associated with a sub-therapeutic concentrations.
Further, lack of appetite, nausea and/or frequent emesis are commonly experienced by patients undergoing withdrawal from narcotic or alcohol abuse and those suffering from chronic, under-treated or intractable pain. As such, oral and sublingual therapies for these patients are often either poorly tolerated or fail to provide an effective therapeutic dose.
For these patients, transdermal administration can provide a favorable route of administration. Transdermal dosing, provides the patient with a desirable systemic delivery profile which can minimize or eliminate any “highs” (dizziness and drowsiness) associated with more rapid absorption and can reduce the side effects associated with oral administration of a drug such as abdominal pain, nausea and vomiting. Additionally, transdermal administration avoids first-pass metabolism which can allow for higher therapeutic concentrations to be achieved. Transdermal delivery also offers a patient freedom from injections and surgical implantations. Transdermal delivery can also improve patient compliance by reducing the dose frequency. A transdermal patch can offer sustained release of a drug for an extended period (e.g., one week) while transdermal gels are also an accepted dosage form for convenient daily application.
Because of the inherent potential for abuse, it is important that any pharmaceutical composition containing an opioid agonist be made as abuse-resistant or abuse-deterrent as possible. This is particularly true with extended release opioid products, including transdermal applications. Illicit users often will attempt to circumvent the extended release properties of these dosage forms by injecting or otherwise misusing the product in order to achieve an immediate release of the opioid agonist.
Not all opioids however are capable of dermal absorption. Buprenorphine, for example, has been evaluated for transdermal delivery, but has generally been found to be too hydrophobic to cross the skin at a therapeutic rate through a reasonably-sized transdermal patch. However, as transdermal pharmaceutical compositions pass through the epidermis and dermis of many mammals, such as humans and guinea pigs, they are exposed to enzymes which are capable of metabolizing active pharmaceutical agents. The metabolic processes occurring in the skin of mammals, such as humans, can be utilized to deliver pharmaceutically effective quantities of opioids to a mammal in need thereof, by metabolizing prodrugs into active pharmaceutical compounds. Thus, it would be desirable to deliver prodrugs of buprenorphine through the skin at a higher rate than buprenorphine while taking advantage of the rapid hydrolysis of the buprenorphine prodrug to buprenorphine during transport into and through the skin. It would be further desirable to combine the buprenorphine prodrug with a non-dermally absorbable prodrug of an opioid antagonist, such as naltrexone, in order to increase the abuse deterrence of the composition.